Sonic Hedgehog Regulates Discrete Populations of Astrocytes in the Adult Mouse Forebrain

Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York 10065, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2010; 30(41):13597-608. DOI: 10.1523/JNEUROSCI.0830-10.2010
Source: PubMed


Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrain in vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron-astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes.

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    • "The mosaic nature of the Cre recombination detects a relative ratio of expressing cells in a given population, rather than absolute numbers. In the normal adult mouse CNS, Gli1-CreERT2 mice have provided important insights into the role of Shh in self-renewal and multipotentiality of neural stem cells and in regulating astrocytic phenotypes (Ahn and Joyner, 2005; Garcia et al., 2010; Ihrie et al., 2011). Gli1-CreERT2 fate mapping of Shh pathway activation has not previously been studied in the context of CNS pathology. "
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    ABSTRACT: The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreER(T2);R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ.
    ASN Neuro 07/2014; 6(5). DOI:10.1177/1759091414551782 · 4.02 Impact Factor
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    • "In the Emx1-Shh cKO, Gli1-nLacZ+ cells (likely due to the slow turnover of nLacZ) were also detected in a region slightly away from the VZ of the ventral hippocampus (arrows in Figure 4F 0 ), as in the control (arrows in Figure 4D 0 ). It has been reported that Gli1-nLacZ expression is affected by the functional copy number of Shh (Garcia et al., 2010). We reasoned that different copy numbers of Shh and Gli1-nLacZ would give us further insights into the formation of Gli1-nLacZ+ cell stream from the VZ of the ventral hippocampus and the de novo induction of Hh-responding cells in the forming DG. "
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    ABSTRACT: Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus.
    Neuron 04/2013; 78(4). DOI:10.1016/j.neuron.2013.03.019 · 15.05 Impact Factor
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    • "Shh expression has also been observed in both the juvenile and adult cerebral cortex (Charytoniuk et al., 2002) outside of known progenitor zones. Recently Shh expression has also been identified in cortical pyramidal neurons (Garcia et al., 2010). However, the function Shh in cortical neurons and the type of neurons expressing Shh remained unknown. "
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    ABSTRACT: The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. VIDEO ABSTRACT:
    Neuron 03/2012; 73(6):1116-26. DOI:10.1016/j.neuron.2012.02.009 · 15.05 Impact Factor
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